CN1938020A - Ion channel modulators - Google Patents

Ion channel modulators Download PDF

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CN1938020A
CN1938020A CNA2005800073891A CN200580007389A CN1938020A CN 1938020 A CN1938020 A CN 1938020A CN A2005800073891 A CNA2005800073891 A CN A2005800073891A CN 200580007389 A CN200580007389 A CN 200580007389A CN 1938020 A CN1938020 A CN 1938020A
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compound
optionally substituted
independently selected
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heteroaryl
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R·泽尔
V·P·加卢洛
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Wyeth LLC
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Abstract

The invention relates to compounds, compositions comprising the compounds, and methods of using the compounds and compound compositions. The compounds, compositions, and methods described herein can be used for the therapeutic modulation of ion channel function, and treatment of disease and disease symptoms, particularly those mediated by certain calcium channel subtype targets.

Description

Ion channel modulators
Background
All cells rely on the regulated movement of inorganic ions across cell membranes to perform basic physiological functions. Electrical excitability, synaptic plasticity and signal transduction are examples of processes in which changes in ion concentration play a critical role. Typically, ion channels that allow for these changes are protein pores consisting of one or more subunits, each containing two or more transmembrane domains. By virtue of the physical preference for size and charge, most ion channels are specific to particular ions, primarily Na+，K+，Ca2+Or Cl-Has selectivity. Electrochemical forces drive ions across membranes rather than actively transporting, so a single channel can allow millions of ions to pass per second. The channel opening, or "gating", is tightly controlled by voltage changes or ligand binding, depending on the subclass of the channel. Ion channels are attractive therapeutic targets because they are involved in so many physiological processes, however, the generation of drugs specific for a particular channel in a particular tissue type becomes a major challenge.
Voltage-gated ion channels open in response to changes in membrane potential. For example, depolarization of excitable cells such as neurons results in Na+The instantaneous influx of ions, which propagates nerve impulses. This Na salt+Voltage-gated K for changes in ion concentration+Channel sensing, the K+Channel then allows K+And (4) ion outflow. K+The flux of ions repolarizes the membrane. Other cell types depend on voltage-gated Ca2+The channel generates an action potential. Voltage-gated ion channels inAlso important roles have been played in non-excitable cells, such as regulation of secretion, homeostasis, mitogenic processes. Ligand-gated ion channels can be stimulated either extracellularly, such as by neurotransmitters (e.g., glutamate, 5-hydroxytryptamine, acetylcholine), or intracellularly (e.g., cAMP, Ca)2+And phosphorylation).
Ca for voltage-gated calcium channelsvFamily 2 consists of 3 major subclasses Cav2.1 (calcium flux of the P or Q type), Cav2.2 (class N calcium flux) and Cav2.3 (class R calcium flow). These calcium currents are present almost exclusively in the Central Nervous System (CNS), Peripheral Nervous System (PNS) and neuroendocrine cells, and constitute the predominant form of presynaptic voltage-gated calcium currents. Presynaptic calcium entry is regulated by many types of G-protein coupled receptors (GPCRs), while CavModulation of 2 channels is a widely distributed and highly effective way of modulating neurotransmission. CavThe composition of the subunits of the 2-channel consists of their alpha1Subunit-the alpha1The subunits form pores and contain voltage sensitive gates (alpha)12.1，α12.2 and α12.3, also referred to as alpha, respectively1A，α1BAnd alpha1E) -and β, α2δ and γ subunits.
Genetic or pharmacological interference with ion channel function can have significant clinical consequences. Long QT syndrome, epilepsy, cystic fibrosis and paroxysmal ataxia are a few examples of genetic disorders resulting from mutations in ion channel subunits. Toxic side effects caused by certain drugs, such as arrhythmias and seizures, are due to interference with ion channel function (Sirois, J.E. and Atchison, W.D., Neuromicrobiology 1996; 17 (1): 63-84; Keting, M.T., Science 1996272: 681-. The medicament can be used for the therapeutic modulation of ion channel activity, and can be used for the treatment of a number of pathologies, including hypertension, angina pectoris, myocardial ischemia, asthma, overactive bladder, alopecia, pain, heart failure, dysmenorrhea, type II diabetes, arrhythmia, transplant rejection, seizure, convulsions, epilepsy, stroke, hypermotility of the stomach, psychosis, and the likeCancer, dystrophia and narcolepsy attacks (Coghlan, M.J. et al, J.Med.chem.2001, 44: 1627-.N.Eng.J.Med.1997, 336: 1575-1586). An increasing number of defined ion channels and an understanding of their complexity will contribute to future therapeutic efforts in altering ion channel function.
CavTherapeutic modulation of 2-channel activity is useful in the treatment of many pathologies. All major sensory afferents are input to neurons in the dorsal horn of the spinal cord and dorsal root ganglion neurons in the dorsal horn, and calcium is transported by Cav2.2 channel inflow triggers the release of neurotransmitters from presynaptic nerve terminals in the spinal cord. Therefore, Ca is expectedvBlockade of the 2.2 channels is broadly effective because these channels are downstream of a common pathway, forming various pain-mediating receptors (Julius, D. and Basbaum, A.I. Nature 2001, 413: 203-. Indeed, Ca has been demonstratedv2.2 intrathecal injection of selective conopeptides (conopeptides) and ziconotides (SNX-111) is broadly effective against neuropathic and inflammatory pain in animals and humans (Bowersox, s.s. et al,J Pharmacol Exp Ther1996, 279: 1243-1249). It has also been shown that ziconotide is very effective as a neuroprotective agent in rat models of systemic and ischemia (Colburn, F. et al, Stroke1999, 30: 662-668). Therefore, it can be reasonably concluded that Cav2.2 modulation suggests a neuroprotective/stroke therapeutic effect.
Cav2.2 channels are present in the peripheral and mediated catecholamine release from sympathetic and adrenal chromaffin (chromaffin) cells. Some forms of hypertension are caused by elevated sympathetic tone, while Cav2.2 modulators are particularly effective in treating this condition. Although Ca was completely blockedv2.2 it can cause hypotension or impair the baroreceptor reflex, but with Cav2.2 partial inhibition by modulators can reduce blood pressure with minimal reflex tachycardia. (Uneyama, O.D.Int.J.mol.Med.19993: 455-466).
Overactive bladder (OAB) is characterized by reserve symptoms such as urgency, frequency and nocturia, with or without urge incontinence (urge incontinence), caused by overactivity of the detrusor muscle of the bladder. OAB can lead to urge incontinence. The etiology of OAB and painful bladder syndrome is unknown, but disturbances of nerves, smooth muscle and urothelium can cause OAB (Steers, w.rev Urol, 4: S7-S18). There is evidence that a decrease in overactive bladder may be indirectly affected by Cav2.2 and/or Cav1 channel inhibition.
Cav2.1 localization of the channels in the superficial layers of the dorsal horn of the spinal cord indicates that these channels are implicated in the perception and maintenance of certain forms of pain (Vanegas, H. and Schaible, H.Pain2000, 85: 9-18. Ca)v2.1 complete elimination of calcium flow alters synaptic transmission, resulting in severe ataxia. Gabapentin has been used clinically for many years as an additional therapeutic agent for the treatment of epilepsy. In recent years, it has emerged as the primary therapeutic agent for neuropathic pain. Clinical trials have shown that gabapentin is effective in the treatment of post-herpetic neuralgia, diabetic neuropathy, trigeminal neuralgia, migraine and fibromyalgia (fibrosagia) (Mellegers, P.G., et al, Clin JPain2001, 17: 284-295). Gabapentin is designed as a metabolically stable GABA mimetic, but most studies found no effect on GABA receptors. Cav2.1 alpha of channel2The delta subunit has been identified as a high affinity binding site for gabapentin in the CNS. There is evidence that gabapentin passes through the interference subunit alpha2δ, thereby inhibiting presynaptic calcium flow and enabling inhibition of neurotransmission in the spinal cord.
SUMMARY
The present invention relates to heterocyclic compounds, compositions comprising the compounds, and methods of using the compounds and compound compositions. The compounds and compositions comprising them are useful for treating diseases or disease symptoms, including those mediated by or associated with ion channels.
One aspect is a compound of formula (I) or a pharmaceutically acceptable salt thereof:
Figure A20058000738900071
wherein,
R3is Ar1Or Ar1-X-Y, wherein
Each Ar1Is cycloalkyl, aryl, heterocyclyl or heteroaryl, each optionally substituted with one or more substituents;
x is NR4，C(R4)2Or O;
y is C ═ O or lower alkyl;
R1is Ar2Or is optionally substituted with Ar2A substituted lower alkyl group,
each Ar2Independently is cycloalkyl, aryl, heterocyclyl or heteroaryl, each optionally substituted with one or more substituents;
each R2Independently selected from (CH)2)mC(O)OR4，(CH2)mC(O)Ar3，(CH2)mC(O)NR4R5，(CH2)nNR4R5，(CH2)3Ar3Or (CH)2)mAr3；
Each R4Independently selected from H or lower alkyl;
each R5Independently selected from H, lower alkyl or (CH)2)pAr3；
m is 1 or 2;
n is 2 or 3;
p is 0 or 1;
each Ar3Is cycloalkyl, aryl, heterocyclyl or heteroaryl, each optionally substituted with one or more substituents;
Ar1、Ar2and Ar3Each substituent of (A) is independently selected from halogen, CN, NO2，OR6，SR6，S(O)2OR6，NR6R7Cycloalkyl radical, C1-C2Perfluoroalkyl radical, C1-C2Perfluoroalkoxy, 1, 2-methylenedioxy, C (O) OR6，C(O)NR6R7，OC(O)NR6R7，NR6C(O)NR6R7，C(NR6)NR6R7，NR6C(NR7)NR6R7，S(O)2NR6R7，R8，C(O)R8，NR6C(O)R8，S(O)R8Or S (O)2R8；
Each R6Independently selected from hydrogen or lower alkyl, said lower alkyl being optionally substituted by one or more groups independently selected from halogen, OH, C1-C4Alkoxy radical, NH2，C1-C4Alkylamino radical, C1-C4Dialkylamino or C3-C6A substituent in a cycloalkyl group;
each R7Independently selected from hydrogen, (CH)2)qAr4Or lower alkyl optionally substituted by one or more substituents independently selected from halogen, OH, C1-C4Alkoxy radical, NH2，C1-C4Alkylamino radical, C1-C4Dialkylamino or C3-C6A substituent in a cycloalkyl group;
each R8Independently selected from (CH)2)qAr4Or lower alkyl optionally substituted by one or more substituents independently selected from halogen, OH, C1-C4Alkoxy radical, NH2，C1-C4Alkylamino radical, C1-C4Dialkylamino or C3-C6A substituent in a cycloalkyl group;
each Ar4Independently selected from C3-C6Cycloalkyl, aryl or heteroaryl, each optionally substituted by one to three substituents independently selected from halogen, OH, C1-C4Alkoxy radical, NH2，C1-C4Alkylamino radical, C1-C4Dialkylamino or C3-C6A substituent in a cycloalkyl group; and
q is 0 or 1.
Another aspect is any compound of the formulae herein (including combinations thereof):
wherein R is3Is Ar1，R1Is Ar2；
Wherein,
R3independently is aryl or heteroaryl, each optionally substituted with one or more substituents; and
R1independently is aryl or heteroaryl, each optionally substituted with one or more substituents;
wherein R is2Is (CH)2)mC(O)OR4，(CH2)mC(O)Ar3Or (CH)2)mC(O)NR4R5；
Wherein R is2Is (CH)2)mAr3，Ar3Is aryl or heteroaryl, each optionally substituted with one or more substituents;
wherein R is2Is (CH)2)mC(O)NR4R5，R5Independently is (CH)2)pAr3Wherein Ar is3Is aryl or heteroaryl, each of which is optionally substituted by one or more substituents；
Wherein R is2Is (CH)2)nNR4R5Or (CH)2)mAr3；
Wherein m is 2 and Ar3Is heteroaryl, comprising a five-membered ring containing carbon atoms and 1, 2 or 3 heteroatoms selected from N, O and S, and optionally substituted with one or more substituents;
wherein Ar is3Is pyrrolidinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, each optionally substituted with one or more substituents; or
Wherein the compound of formula I is any of the compounds in tables 1-6.
Another aspect is a composition comprising a compound of formula I and a pharmaceutically acceptable carrier. The composition may further comprise other therapeutic agents.
Another aspect is a method of treating a disease or disease symptom in a patient in need of such treatment, the method comprising administering to the patient an effective amount of a compound of any of the formulae herein. The method can be a method wherein the disease or disease symptom is modulated (e.g., inhibited, agonized, antagonized) by a calcium channel Cav2 (e.g., Cav 2.2). The disease or disease symptom may be angina pectoris, hypertension, congestive heart failure, myocardial ischemia, arrhythmia, diabetes, urinary incontinence, stroke, pain, brain trauma or a neuronal disorder.
In other aspects, the invention is a method of modulating (e.g., inhibiting, agonizing, antagonizing) calcium channel activity comprising contacting a calcium channel with a compound of any of the formulae herein; a method of modulating the activity of a calcium channel Cav2 (e.g., Cav2.2) in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of any of the formulae herein (or a composition thereof).
In other aspects, the invention relates to compositions comprising a compound of any of the formulae herein, an additional therapeutic agent, and a pharmaceutically acceptable carrier. The other therapeutic agent may be a therapeutic agent for cardiovascular diseases and/or a therapeutic agent for nervous system diseases. The therapeutic agent for nervous system diseases refers to a therapeutic agent for Peripheral Nervous System (PNS) diseases and/or a therapeutic agent for Central Nervous System (CNS) diseases.
Yet another aspect of the invention relates to a method of treating a patient (e.g., mammal, human, horse, dog, cat) suffering from a disease or disease symptom (including, but not limited to angina pectoris, hypertension, congestive heart failure, myocardial ischemia, arrhythmia, diabetes, urinary incontinence, stroke, pain, brain trauma or a neuronal disorder). The method comprises administering to a patient (including a patient identified as in need of such treatment) an effective amount of a compound described herein or a composition described herein that produces such an effect. The determination of a patient in need of such treatment may be at the discretion of the patient or health care professional, and may be subjective (e.g., opinion) or objective (e.g., as determined by a test or diagnostic method).
Yet another aspect of the invention relates to a method of treating a patient (e.g., mammal, human, horse, dog, cat) suffering from an ion channel mediated disease or disease symptom (including, but not limited to, angina, hypertension, congestive heart failure, myocardial ischemia, arrhythmia, diabetes, urinary incontinence, stroke, pain, brain trauma, or a neuronal disorder). The method comprises administering to a patient (including a patient identified as in need of such treatment) an effective amount of a compound described herein or a composition described herein that produces such an effect. The determination of a patient in need of such treatment may be at the discretion of the patient or health care professional, and may be subjective (e.g., opinion) or objective (e.g., as determined by a test or diagnostic method).
The present invention also relates to methods of making the compounds described herein, including any of the reactions or reagents as described in the schemes or examples herein. Alternatively, the method comprises taking any one of the intermediate compounds described herein and reacting it with one or more chemical reagents in one or more steps, thereby preparing the compound described herein.
Packaged products are also within the scope of the invention. The packaged product comprises a container within which is located one of the above-mentioned compounds and instructions (e.g. a label or insert) associated with the container and indicating administration of the compound for use in the treatment of a disease associated with ion channel modulation.
In other embodiments, the compounds, compositions, and methods described herein are any compounds in the tables herein or methods that include them.
The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims.
Detailed Description
The term "halogen" as used herein refers to any fluorine, chlorine, bromine or iodine group.
The term "alkyl" refers to a hydrocarbon chain that may be straight or branched and contains the indicated number of carbon atoms. E.g. C1-C5Meaning that the group may have from 1 to 5 (inclusive) carbon atoms. The term "lower alkyl" refers to C1-C6An alkyl chain. The term "aralkyl" refers to a moiety in which an alkyl hydrogen atom is replaced with an aryl group.
The term "alkoxy" refers to-O-alkyl. The term "alkylene" refers to a divalent alkyl group (i.e., -R-). The term "alkylenedioxy" refers to a divalent species of the formula-O-R-O-, wherein R represents an alkylene group.
The term "cycloalkyl" as used herein includes saturated and partially unsaturated cyclic hydrocarbon groups having from 3 to 12 carbon atoms, preferably from 3 to 8 carbons, more preferably from 3 to 6 carbons.
The term "aryl" refers to a 6-membered monocyclic or 10-14 membered polycyclic aromatic hydrocarbon ring system wherein 0, 1, 2, 3 or 4 atoms of each ring may be substituted by a substituent. Examples of aryl groups include phenyl, naphthyl, and the like.
The term "heterocyclyl" refers to a non-aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O or S in the case of monocyclic, bicyclic, or tricyclic rings, respectively), wherein 0, 1, 2, or 3 atoms of each ring can be substituted with a substituent.
The term "heteroaryl" refers to an aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N or S (e.g., carbon atoms and 1-3, 1-6, or 1-9N, O or S heteroatoms in the case of monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted with a substituent.
The term "oxo" refers to an oxygen atom which when attached to carbon forms a carbonyl, when attached to nitrogen forms an N-oxide, and when attached to sulfur forms a sulfoxide or sulfone.
The term "acyl" refers to an alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl, or heteroarylcarbonyl substituent, all of which may be further substituted with a substituent.
The term "substituent" refers to a group that is "substituted" on any atom of an alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl group. Suitable substituents include, but are not limited to, halogen, CN, NO2，OR5，SR5，S(O)2OR5，NR5R6，C1-C2Perfluoroalkyl radical, C1-C2Perfluoroalkoxy, 1, 2-methylenedioxy, C (O) OR5，C(O)NR5R6，OC(O)NR5R6，NR5C(O)NR5R6，C(NR6)NR5R6，NR5C(NR6)NR5R6，S(O)2NR5R6，R7，C(O)R7，NR5C(O)R7，S(O)R7Or S (O)2R7. Each R5Independently of one another is hydrogen, C1-C4Alkyl or C3-C6A cycloalkyl group. Each R6Independently of one another is hydrogen, C3-C6Cycloalkyl, aryl, heterocyclyl, heteroaryl, C1-C4Alkyl or by C3-C6Cycloalkyl, aryl, heterocyclyl or heteroaryl substituted C1-C4An alkyl group. Each R7Independently is C3-C6Cycloalkyl, aryl, heterocyclyl, heteroaryl, C1-C4Alkyl or by C3-C6Cycloalkyl, aryl, heterocyclyl or heteroaryl substituted C1-C4An alkyl group. At each R5、R6And R7Each C in (1)3-C6Cycloalkyl, aryl, heterocyclyl, heteroaryl and C1-C4Alkyl may optionally be substituted by halogen, CN, C1-C4Alkyl, OH, C1-C4Alkoxy, NH2、C1-C4Alkylamino radical, C1-C4Dialkylamino radical, C1-C2Perfluoroalkyl radical, C1-C2Perfluoroalkoxy, or 1, 2-methylenedioxy.
In one aspect, the substituents on the groups are independently hydrogen, hydroxy, halogen, nitro, SO3H, trifluoromethyl, trifluoromethoxy, alkyl (C1-C6 straight or branched), alkoxy (C1-C6 straight or branched), O-benzyl, O-phenyl, 1, 2-methylenedioxy, carboxy, morpholinyl, piperidinyl, amino or OC (O) NR5R6。R5And R6Each as described above.
The term "treatment" or "therapeutic" refers to the administration of a compound described herein to a patient for the purpose of treating, curing, alleviating, altering, correcting (remedy), ameliorating, improving or affecting a disease, a symptom of a disease, or a predisposition to a disease.
An "effective amount" refers to an amount of a compound that provides a therapeutic effect to a treated patient. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., the patient gives an indication of the effect or feels the effect). An effective amount of the above compound may be about 0.1mg/Kg to about 500 mg/Kg. The effective dosage will also vary depending on the route of administration and the possibility of co-use with other agents.
Representative compounds useful in the compositions and methods are depicted herein:
TABLE 1
Figure A20058000738900131
Figure A20058000738900132
Figure A20058000738900151
Figure A20058000738900171
Figure A20058000738900181
Figure A20058000738900191
Figure A20058000738900201
Figure A20058000738900211
Figure A20058000738900221
TABLE 2
Figure A20058000738900222
Figure A20058000738900223
Figure A20058000738900241
Figure A20058000738900251
Figure A20058000738900261
Figure A20058000738900271
Figure A20058000738900281
Figure A20058000738900301
Figure A20058000738900311
TABLE 3
Figure A20058000738900312
Figure A20058000738900321
Figure A20058000738900341
Figure A20058000738900351
Figure A20058000738900361
Figure A20058000738900371
TABLE 4
Figure A20058000738900421
Figure A20058000738900451
Figure A20058000738900461
Figure A20058000738900471
Figure A20058000738900481
TABLE 5
Figure A20058000738900502
Figure A20058000738900503
Figure A20058000738900511
Figure A20058000738900521
Figure A20058000738900531
Figure A20058000738900541
Figure A20058000738900551
Figure A20058000738900561
Figure A20058000738900571
Figure A20058000738900581
Figure A20058000738900591
TABLE 6
Figure A20058000738900592
Figure A20058000738900593
Figure A20058000738900601
Figure A20058000738900611
Figure A20058000738900621
Figure A20058000738900631
Figure A20058000738900651
Figure A20058000738900671
Ion channel modulating compounds can be identified by in vitro (e.g., cell or non-cell type) and in vivo methods. Representative examples of these methods are described in the examples herein.
Combinations of substituents and variables contemplated by the present invention are only those that result in the formation of stable compounds. The term "stable" as used herein refers to a compound that is sufficiently stable to allow manufacture and maintenance of the integrity of the compound for a sufficient period of time to be useful for the purposes described in detail herein (e.g., therapeutic or prophylactic administration to a patient).
The compounds described herein can be synthesized using conventional methods as shown in the following reaction schemes. In the reaction schemes herein, unless explicitly stated to the contrary, chemistryThe variables in the formulae are as defined in the other formulae herein. For example, Ar in the reaction scheme is not specifically defined in the reaction scheme1、Ar3、R1、R3And R4As defined for any chemical formula herein.
Reaction scheme 1
Figure A20058000738900692
The bromomethyl compound is treated with sodium azide to obtain an azidomethyl compound (I). (I) Under reducing conditions (e.g. palladium on carbon) in aqueous HCl and H2The treatment under atmosphere gives the amine (II). (II) treatment with isothiocyanate (III) affords Imidazole (IV). The N-alkylated imidazole (VIa) is prepared from the reaction of (IV) with 3-bromo-propionate or 4-bromo-butyrate (V). Saponification of the ester (VIa) yields the carboxylic acid (VIb).
Reaction scheme 2
Figure A20058000738900701
Alternatively, Imidazole (IV) is prepared by the following procedure. Ethyl diethoxyacetate (VII) is treated with hydrazine in a solvent (e.g. ethanol) to obtain hydrazide (VIII). (VIII) treatment with a thioisocyanate (III) under aqueous basic conditions gives an Imidazole (IX) and further under aqueous acidic conditions an aldehyde (X). Reductive amination of (X) and amine (XI) affords (IV).
Reaction scheme 3
Figure A20058000738900702
Reaction of carboxylic acid (VIb) with an appropriately substituted amine under standard coupling procedures affords the desired amide (XII). The amide is reduced under common reduction conditions (e.g., diborane or lithium aluminum hydride) to afford the corresponding amine (XIII). Alternatively, (VIb) treatment with Weinreb reagent gives the amide (XIV). Amide (XIV) is treated with an organometallic reagent (e.g., an aryl lithium or aryl magnesium halide) under standard conditions to afford ketone (XV). The ketone is reduced under various conditions to obtain the desired product (XVI).
Reaction scheme 4
Figure A20058000738900711
Ester (VIa) is treated under standard reducing conditions (e.g., lithium aluminum hydride) to afford alcohol (XVII). (XVII) is treated under standard ether forming conditions (e.g., NaH, benzyl bromide) to provide (XVIII).
Reaction scheme 5
Figure A20058000738900712
An alternative route to obtain heteroaryl derivatives is to react the activated acid of (VIb) with an appropriate substrate followed by cyclization to obtain the desired product. For example, as shown in scheme 5, the reaction of the activated acid of (VIb) with benzene-1, 2-diamine provides an intermediate amide (XIX) which undergoes cyclization to give the benzimidazole derivative (XX).
The synthesized compound may be isolated from the reaction mixture and further purified by a method such as column chromatography, high pressure liquid chromatography or recrystallization. As will be appreciated by those skilled in the art, other methods of synthesizing the compounds of the formulae herein are within the skill of those of ordinary skill in the artAs will be apparent. In addition, the various synthetic steps may be performed in an alternating (alternate) sequence or order to obtain the desired compound. Synthetic chemical transformations and protecting group methods (protection and deprotection) useful in the synthesis of the compounds described herein are known in the art and include, for example, in rComprehensive Organic Transformations) ", 2 nd edition, Wiley-VCH Publishers (1999); t.w.greene and p.g.m.wuts, "protecting groups in organic synthesis: (Protective Groups in Organic Synthesis) ", 3 rd edition, John Wiley and Sons (1999); fieser and m.fieser, "Fieser reagents for organic synthesis: (Fieser and Fieser′s Reagents for Organic Synthesis) ", John Wiley and Sons (1999); and L.Patquette, ed., "encyclopedia of organic Synthesis reagentsEncyclopedia of Reagents for Organic Synthesis) ", John Wiley and Sons (1995), and subsequent versions thereof.
The compounds of the invention may contain one or more asymmetric centers and thus exist as racemates or racemic mixtures, single enantiomers, single diastereomers and diastereomeric mixtures. All such isomeric forms of these compounds are expressly included in the present invention. The compounds of the present invention may also be represented in multiple tautomeric forms, in such cases, the present invention expressly includes all tautomeric forms of the compounds described herein (e.g., alkylation of a ring system may result in alkylation of multiple positions, the present invention expressly includes all such reaction products). All such isomeric forms of these compounds are expressly included in the present invention. All crystal forms of the compounds described herein are expressly included in the present invention.
The compounds of the invention, including compounds of the formulae described herein, as used herein, are defined as including pharmaceutically acceptable derivatives or prodrugs thereof. "pharmaceutically acceptable derivative or prodrug" refers to any pharmaceutically acceptable salt, ester, prodrug, or salt of a compound of the invention,Salts or other derivatives of esters, when administered to a recipient, are capable of providing (directly or indirectly) a compound of the invention. Particularly advantageous derivatives and prodrugs are those that increase the bioavailability of the compounds of the invention when administered to a mammal (e.g., by allowing the oral compound to be more readily absorbed into the blood) or which enhance transport of the parent compound to a biological compartment (e.g., the brain or lymphatic system) as compared to the parent species. Preferred prodrugs include derivatives wherein a group that enhances water solubility or transport of the active ingredient through the intestinal membrane is attached to the structure of the formulae described herein. See, for example, Alexander, J. et al, "J. chem. J. (Journal of Medicinal Chemistry) "1988, 31, 318-; bundgaard, h. "prodrug designDesign of Prodrugs) "; elsevier: amsterdam, 1985; pages 1-92; bundgaard, h.; nielsen, N.M. "Journal of pharmaceutical chemistry" 1987, 30, 451-; bundgaard, H.A "Drug Design and Development tutorial (a Textbook of Drug Design and Development)"; harwood A typical publish: switzerland, 1991; page 113 and 191; digenis, g.a. et al, "Handbook of Experimental Pharmacology" 1975, 28, 86-112; friis, g.j.; bundgaard, H.A "Drug Design and Development tutorial (atextwood of Drug Design and Development)"; version 2; overturas pub.: amsterdam, 1996; page 351-; pitman, i.h. "pharmaceutical Research Reviews" 1981, 1, 189-; sinkula, a.a.; yalkowsky, "Journal of Pharmaceutical Sciences" 1975, 64, 181-210; verbiscar, a.j.; abood, L.G "Journal of medicinal Chemistry" 1970, 13, 1176-; stella, v.j.; himmelstein, K.J. "Journal of Medicinal Chemistry" 1980, 23, 1275-; bodor, n.; "annual reports of Medicinal Chemistry (annual reports in Medicinal Chemistry)" 1987, 22, 303-313 of Kaminski, J.J.
The compounds of the present invention may be modified by the attachment of appropriate functional groups to enhance selective biological properties. Such modifications are known in the art and include those that increase biological penetration to a given biological compartment (e.g., blood, lymphatic system, nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism, and alter rate of excretion.
Pharmaceutically acceptable salts of the compounds of the present invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmitate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate, and undecanoate. Other acids, such as oxalic, while not per se pharmaceutically acceptable, may be used to prepare salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts. Salts obtained with a suitable base include alkali metal (e.g., sodium) salts, alkaline earth metal (e.g., magnesium) salts, ammonium salts and N- (alkyl)4 +And (3) salt. The present invention also contemplates the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or oil-dispersible products can be obtained by such quaternization.
The compounds of the formulae described herein can be administered, for example, by injection, intravenously, intraarterially, subcutaneously (subdermally), intraperitoneally, intramuscularly, or subcutaneously; or orally, buccally, nasally, transmucosally, topically, in ophthalmic preparations or by inhalation, in a dose of about 0.5 to about 100mg/kg of body weight, or in a dose of 1mg to 1000mg per dose, every 4 to 120 hours, or as required by the particular drug. The methods described herein contemplate administration of an effective amount of a compound or compound composition to achieve a desired or specified effect. Typically, the pharmaceutical compositions of the present invention are administered from about 1 to about 6 times daily, or continuously. Such administration can be used as a chronic or acute treatment. The amount of active ingredient that can be combined with the carrier materials to form a single dosage form will vary depending upon the host treated and the particular mode of administration. Typical formulations contain from about 5 to about 95% active compound (w/w). Alternatively, such formulations contain from about 20 to about 80% active compound.
Lower or higher doses than those described above may be required. The specific dose and treatment regimen for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptom, the patient's susceptibility to the disease, condition or symptom (disposition), and the judgment of the treating physician.
In ameliorating the condition of the patient, a maintenance dose of a compound, composition or conjugate of the invention may be administered, if necessary. Subsequently, depending on the symptoms, the dose or frequency of administration, or both, can be reduced to a level that maintains an improved condition, and treatment should be discontinued when the symptoms have been alleviated to a desired level. However, upon recurrence of disease symptoms, the patient may require long-term intermittent treatment.
The compositions described herein comprise a compound of the formulae described herein and other therapeutic agents, if present, in an amount effective to modulate the disease or disease symptoms, including ion channel mediated diseases or symptoms. References including examples of other therapeutic agents are: 1) "Burger's Medicinal Chemistry & drug discovery" 6 th edition, Alfred Burger, Donald J.Abraham, ed., Vol.1-6, Wiley Interscience Publication, NY, 2003; 2) "ion channels and diseases (ion channels and diseases)", Francis m.ashcroft, Academic Press, NY, 2000; and 3) "Calcium Antagonists in clinical medicine (Calcium Antagonists in clinical medicine" 3 rd edition, Murray Epstein, MD, FACP, ed., Hanley & Belfus, inc. Other therapeutic agents include, but are not limited to, agents for treating cardiovascular diseases (e.g., hypertension, angina, etc.), metabolic diseases (e.g., syndrome X, diabetes, obesity), pain (e.g., severe pain, inflammatory pain, neuropathic pain, migraine, etc.), renal or genitourinary diseases (e.g., glomerulonephritis, urinary incontinence, nephrotic syndrome), abnormal cell growth (e.g., tumors, fibrotic diseases), neurological diseases (e.g., epilepsy, stroke, migraine, brain trauma or neuronal disorders, etc.), respiratory diseases (e.g., asthma, COPD, pulmonary hypertension) and disease symptoms thereof. Examples of other therapeutic agents for treating cardiovascular diseases and disease symptoms include, but are not limited to, antihypertensive agents, ACE inhibitors, angiotensin II receptor antagonists, statins, beta receptor blockers, antioxidants, anti-inflammatory agents, antithrombotic agents, anticoagulants or antiarrhythmic agents. Examples of other therapeutic agents for the treatment of metabolic diseases and disease symptoms include, but are not limited to, ACE inhibitors, angiotensin II antagonists, fibrates, thiazolidinediones or sulfonylurea antidiabetic agents. Examples of other therapeutic agents for treating pain and its symptoms include, but are not limited to, non-steroidal anti-inflammatory drugs ("NSAIDS", e.g., aspirin, ibuprofen, flureuptazole, acetaminophen, etc.), opioids (e.g., morphine, fentanyl, oxycodone), and agents such as gabapentin, ziconotide, tramadol, methamphetamine, carbamazepine, baclofen or capsaicin. Examples of other therapeutic agents for the treatment of renal and/or genitourinary syndromes and symptoms thereof include, but are not limited to, alpha 1 adrenergic antagonists (e.g., doxazosin), antimuscarinic agents (e.g., tolterodine), norepinephrine/5-hydroxytryptamine reuptake inhibitors (e.g., duloxetine), tricyclic antidepressants (e.g., doxepin, desipramine) or steroids. Examples of other therapeutic agents for treating abnormal cell growth syndrome and its symptoms include, but are not limited to, anti-cytokine therapeutic agents (e.g., anti-tumor necrosis factor and anti-IL-1 biologics, p38 MAPK inhibitors), endothelin-1 antagonists or stem cell therapeutic agents (e.g., progenitor cells). Examples of other therapeutic agents for treating stroke disease and its symptoms include, but are not limited to, neuroprotective agents and anticoagulants (e.g., alteplase (TPA), abciximab). Examples of other therapeutic agents for treating epilepsy and its symptoms include, but are not limited to, GABA analogs, hydantoins, barbiturates, phenyl triazines, succinimides, valproic acid, carbamazepine, falbamate, and leveracetam. Examples of other therapeutic agents for treating migraine include, but are not limited to, 5-hydroxytryptamine/5-HT receptor agonists (e.g., sumatriptan and the like). Examples of other therapeutic agents for treating respiratory diseases and symptoms thereof include, but are not limited to, anticholinergics (e.g., tiotropium bromide), steroids, anti-inflammatory agents, anti-cytokine agents, or PDE inhibitors.
The term "pharmaceutically acceptable carrier or adjuvant" refers to a carrier or adjuvant that can be administered to a patient with a compound of the present invention and which does not destroy the pharmacological activity of the compound when administered in a dosage sufficient to deliver a therapeutic amount of the compound and which is non-toxic.
Pharmacologically acceptable carriers, adjuvants and excipients which may be used in the pharmaceutical compositions of the invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, Self Emulsifying Drug Delivery Systems (SEDDS), such as d- α -tocopheryl polyethylene glycol 1000 succinate, surfactants for pharmaceutical dosage forms, such as tweens or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances, such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycols and lanolin. Cyclodextrins, such as alpha-, beta-, and gamma-cyclodextrins, or chemically modified derivatives such as hydroxyalkyl cyclodextrins, including 2-and 3-hydroxypropyl-beta-cyclodextrins, or other solubilizing derivatives, may also be advantageously employed to enhance delivery of compounds of the formulas described herein.
The pharmaceutical compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably orally or by injection. The pharmaceutical compositions of the present invention may contain any conventional non-toxic pharmaceutically acceptable carriers, adjuvants or vehicles. In certain instances, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form. The term parenteral as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
The pharmaceutical compositions may be in sterile injectable preparations, for example, as sterile injectable aqueous or oleaginous suspensions. The suspension may be formulated according to the techniques known in the art using suitable dispersing or wetting agents (e.g., tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Acceptable excipients and solvents that may be used include mannitol, water, ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are pharmaceutically-acceptable natural oils, such as olive oil or castor oil, especially polyoxyethylated versions thereof. These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents, which are commonly used to formulate pharmaceutically acceptable dosage forms such as emulsions and/or suspensions. It may also be formulated using other commonly used surfactants such as tweens or spans and/or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid or other dosage forms.
The pharmaceutical compositions of the present invention may be administered orally in any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral capsule dosage forms, useful diluents include lactose and dried corn starch. When aqueous suspensions and/or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oily phase, combined with emulsifying and/or suspending agents. If desired, certain sweeteners and/or flavors and/or colorants may be added.
The pharmaceutical compositions of the present invention may also be used in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing a compound of the invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the active ingredients. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
The pharmaceutical compositions of the present invention may be administered topically when the desired treatment involves an area or organ that is readily accessible by topical application. For topical administration to the skin, the pharmaceutical compositions should be formulated as a suitable ointment with the active ingredient suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this invention include, without limitation, mineral oil, liquid paraffin (liquidetroleum), white mineral wax (white petroleum), propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. In addition, the pharmaceutical compositions can be formulated in suitable lotions or creams in which the active compound is suspended or dissolved in a carrier with suitable emulsifiers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, tween 60, cetyl esters wax, cetyl stearyl alcohol (cetearyl alcohol), 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of the present invention may also be administered topically to the lower intestinal tract by rectal suppository or in a suitable enema. The invention also includes a topical transdermal patch.
The pharmaceutical compositions of the present invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons and/or other solubilizing or dispersing agents known in the art.
Compositions containing the compounds of the formulae herein and other agents (e.g., therapeutic agents) can be administered using implantable devices. Implantable devices and related techniques are known in the art for use as delivery systems where continuous or timed release delivery of a compound or composition described herein is desired. In addition, implantable device delivery systems can be used to target specific sites (e.g., localized sites, organs) for compound or composition delivery. Negrin et al, Biomaterials, 22 (6): 563(2001). Timed release techniques including alternative delivery methods may also be used in the present invention. For example, time release formulations based on polymer technology, sustained release technology, and encapsulation technology (e.g., polymers, liposomes) can also be used to deliver the compounds and compositions described herein.
Patches for delivering active chemotherapeutic conjugates herein are also within the scope of the invention. The patch includes a layer of material (e.g., polymer, cloth, gauze, bandage) and a compound of the formula described herein. One side of the material layer can have a protective layer attached to it to prevent the passage of compounds or compositions. The patch can additionally include an adhesive for holding the patch in place on the patient. An adhesive is a composition, including those of natural or synthetic origin, that temporarily adheres to the skin of a patient when in contact therewith. It can be water resistant. The adhesive can be placed on the patch to keep it in contact with the patient's skin for an extended period of time. The adhesive is capable of developing tack or adhesive strength such that it secures the device in place for temporary contact, however, upon a confirming action (e.g., tearing, peeling or other intentional removal), the adhesive yields to external pressure applied to the device or the adhesive itself, thereby breaking the adhesive contact. The adhesive can be a pressure sensitive material, that is, it can be positioned on the skin (and the device to be attached to the skin) by applying pressure (e.g., pushing, rubbing) on the adhesive or the device.
When the compositions of the present invention comprise a combination of a compound of the formulae described herein and one or more other therapeutic or prophylactic agents, the compound and additional agent should be present at dosage levels of from about 1 to 100%, more preferably from about 5 to 95%, of the dosage normally administered in a single treatment regimen (monopropepy regin). The additional agent may be administered separately from the compound of the invention as part of a multiple dosing regimen. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of the present invention in a single composition.
The invention is further illustrated by the following examples. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting the present invention in any way.
Example 1
Oocyte test
In a state substantially as described in Neuron1997, month 1, 18 (11): 153-166, Lin et al; neurosci.2000, 7/1/20 (13): 4768-75, J.Pan and D.Lipsombe; and j. neurosci, 8/15/2001, 21 (16): 5944-. Assays were performed on a variety of calcium channels (e.g., cav2.2 subfamily) to determine calcium channel modulation for each compound.
Example 2
HEK test
HEK-293T/17 cells were transiently transfected in a manner similar to that described in FuGENE6Package Insert Version7, 4.2002, Indiana Poisson Roche Applied Science. These cells were cultured at 2.5X 105Cells, 2mL amount, were plated on 6-well plates and placed in an incubator overnight to obtain 30-40% fusion. Sufficient serum-free medium was added to a small sterile tube as a diluent for the FuGENE transfection reagent (Rocheapplied Science, Indianapolis, Ind.) to a total volume of 100. mu.L. mu.L of FuGENE6 reagent was added directly to the medium. The mixture was gently tapped to effect mixing. Mu.g of the DNA solution (0.8-2.0. mu.g/. mu.L) was added to the pre-diluted FuGENE6 reagent obtained from above. The DNA/Fugene6 mixture was gently pipetted to mix the contents and incubated at room temperature for approximately 15 minutes. The complex mixture was then added to HEK-293T/17 cells, distributed around the wells, spun to ensure uniform dispersion. The cells were returned to the incubator and held for 24 hours. Transfected cells were then plated at 2.5X 105The density of (D) was replated with 5 glass coverslips in 35mm dishes and grown in low serum (1%) medium for 24 hours. The coverslip with the isolated cells is then transferred to a chamber where calcium channel (e.g., L-type, N-type, etc.) flow or other flow is recorded from transiently transfected HEK-293T/17 cells for reverse screening.
Substantially as described by Thompson and Wong (1991) j. physiol., 439: 671-689 the voltage-dependent calcium flux was evaluated using the whole-cell voltage clamp structure of the membrane-clip technique. To record the flow of calcium channels (e.g., L-type, N-type, etc.) evaluating the inhibitory potency (steady state concentration response assay) of a compound, approximately +10mV (peak current-voltage relationship) was reached starting from a maintenance potential of-100 mV, with a 20-30ms voltage step of 5 pulses delivered at 5Hz every 30 seconds. Essentially as for Sah DW and Bean BP (1994) Mol pharmacol.45 (1): compound evaluations were performed as described in 84-92.
Representative compounds of the general formula herein were evaluated for calcium channel target activity.
Example 3
Formalin test
Representative compounds of the general formulae herein were screened for activity in the formalin test. The formalin test is widely used as a model for acute and stressful inflammatory Pain (Dubuisson & Dennis, 1977Pain 4: 161-174; Wheeler-Aceto et al, 1990, Pain 40: 229-238; Coderre et al, 1993, Pain 52: 259-285). The test involves administration of a dilute formalin solution to the rat hindpaw followed by monitoring behavioral signs (i.e., flinching, biting and licking) in the "late" phase of the formalin response (11-60 minutes post-injection), which reflect both peripheral nerve activity and central sensitization. Male Sprague-Dawley rats (Harlan, Ind. Napolis, Ind.) weighing approximately 225-300g were used, with n being 6-8 per treatment group.
Depending on the pharmacokinetic profile and route of administration, the vehicle or dose of test compound is administered to each rat by intraperitoneal or oral route 30-120 minutes prior to formalin administration. Each animal was acclimatized in the laboratory for 60 minutes prior to formalin administration by injecting 50 μ L of a 5% solution subcutaneously into the plantar surface of one hind paw using a 300 μ L mini-syringe and 29 gauge needle. A mirror is placed at an angle behind the laboratory to enhance viewing of the animal's paw. Following formalin administration, the number of consecutive 2 minutes flinches (paw lifting, with or without rapid paw shaking) and the time taken to bite and/or lick the injured hind paw were recorded for a total of 60 minutes per 5 minutes per rat. Peripheral blood samples were collected for analysis of plasma compound concentrations. Comparisons between groups of total number of flinches or time spent biting and/or licking at early or late stages were performed using one-way analysis of variance (ANOVA).
Example 4
Compound 15
3- (2- (1H-benzo [ d ] imidazol-2-yl) ethyl) -5- (4-fluorophenyl) -1-p-tolyl-1H-imidazole-2 (3H) -thione
Reaction scheme 6
Figure A20058000738900801
Preparation of the moiety 1, 2-azido-1- (4-fluoro-phenyl) -ethanone
A solution of 2-bromo-1- (4-fluoro-phenyl) -ethanone (1 eq) in DMSO was stirred vigorously at 10 ℃ and sodium azide (1.25 eq) was added. The mixture was stirred for 1 hour, then quenched with water and extracted with ethyl acetate (2 ×). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2-azido-1- (4-fluoro-phenyl) -ethanone.
Preparation of part of 2, 2-amino-1- (4-fluoro-phenyl) -ethanone hydrochloride
To a solution of 2-azido-1- (4-fluoro-phenyl) -ethanone in ethanol was added concentrated hcl (aq) and 10% Pd/C (10 mol%). The mixture is reacted with hydrogen (H)2) Stir at 45psi for 1 hour under atmosphere. The mixture was filtered through celite and the celite cake was washed with copious amounts of methanol. The solvent was removed under reduced pressure and the resulting residue was triturated with ether, filtered and dried to give 2-amino-1- (4-fluoro-phenyl) -ethanone hydrochloride.
Preparation of the moiety 3.1- (4-chloro-phenyl) -5- (4-fluoro-phenyl) -1H-imidazole-2-thiol
A mixture of 2-amino-1- (4-fluoro-phenyl) -ethanone hydrochloride (1 equivalent), 4-chlorophenyl isothiocyanate (1 equivalent) and sodium bicarbonate (1.5 equivalents) in ethanol was heated at 90 ℃ for 2 hours. The solvent was removed under reduced pressure. The resulting residue was resuspended in 1N aqueous sodium hydroxide and heated at 100 ℃ overnight. The hot mixture was filtered, cooled and carefully acidified with 6N HCl. The resulting mixture was filtered to obtain 1- (4-chloro-phenyl) -5- (4-fluoro-phenyl) -1H-imidazole-2-thiol.
Part 4.3- (5- (4-fluorophenyl) -1, 2-dihydro-2-thioxo-1-p-tolylimidazol-3-yl) propionitrile
A mixture of 5- (4-fluorophenyl) -1-p-tolyl-1H-imidazole-2-thiol (1 eq) in dioxane was stirred and Triton B was added. The mixture was heated to 70 ℃, acrylonitrile (1 eq) was added and heated for an additional 3 hours. The cooled mixture was partitioned between 0.1N aqueous HCl and ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. Performing flash chromatography (SiO)2) To obtain 3- (5- (4-fluorophenyl) -1, 2-dihydro-2-thio-1-p-tolylimidazol-3-yl) propionitrile.
Preparation of part 5.3- (1- (4-chlorophenyl) -5- (4-fluorophenyl) -1, 2-dihydro-2-thioimidazol-3-yl) propioimidate
A solution of the propionitrile in 1: 1 ethanol/diethyl ether was cooled in an ice-water bath, and HCl (g) was carefully bubbled into the solution over 10-20 minutes. The reaction mixture was stirred at room temperature for 2 to 4 hours, and the solvent was removed under reduced pressure to obtain ethyl 3- (1- (4-chlorophenyl) -5- (4-fluorophenyl) -1, 2-dihydro-2-thioimidazol-3-yl) propanimidate.
Part 6.3- (2- (1H-benzo [ d ] imidazol-2-yl) ethyl) -5- (4-fluorophenyl) -1-p-tolyl-1H-imidazole-2 (3H) -thione preparation
The mixture of alanine ethyl ester and benzene-1, 2-diamine in ethanol was stirred and heated at 60 ℃ overnight. Removing the solvent under reduced pressure; the residue was taken up in ethyl acetate and saturated aqueous sodium bicarbonateAre distributed among the devices. The organic layer was dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. By flash chromatography (SiO)2) Purification followed by formation of the HCl salt (methanol and 2M HCl in ether) to yield 3- (2- (1H-benzo [ d)]Imidazol-2-yl) ethyl) -5- (4-fluorophenyl) -1-p-tolyl-1H-imidazole-2 (3H) -thione hydrochloride.
Compound 22
3- (1- (4-chlorophenyl) -5- (4-fluorophenyl) -1, 2-dihydro-2-thioimidazol-3-yl) propionic acid ethyl ester
Reaction scheme 7
Figure A20058000738900821
Preparation of ethyl 3- (1- (4-chlorophenyl) -5- (4-fluorophenyl) -1, 2-dihydro-2-thioimidazol-3-yl) propionate
To a solution of 1- (4-chloro-phenyl) -5- (4-fluoro-phenyl) -1H-imidazole-2-thiol (1 eq) in DMF was added a 1M solution of lithium bis (trimethylsilyl) amide in THF (1 eq) and ethyl 3-bromopropionate (1 eq). The mixture was heated at 60 ℃ for 2 hours and then cooled to room temperature. The mixture was quenched with water and extracted with ethyl acetate. The organics were dried and concentrated in vacuo. The residue was purified by silica column chromatography to obtain ethyl 3- (1- (4-chlorophenyl) -5- (4-fluorophenyl) -1, 2-dihydro-2-thioimidazol-3-yl) propionate.
Compound 26
3- (1- (4-chlorophenyl) -5- (4-fluorophenyl) -1, 2-dihydro-2-thioimidazol-3-yl) -1- (pyrrolidin-1-yl) propan-1-one
Reaction scheme 8
Figure A20058000738900831
Preparation of part 1.3- (1- (4-chlorophenyl) -5- (4-fluorophenyl) -1, 2-dihydro-2-thioimidazol-3-yl) propionic acid
A mixture of ethyl 3- (1- (4-chlorophenyl) -5- (4-fluorophenyl) -1, 2-dihydro-2-thioimidazol-3-yl) propionate (1 equivalent) and lithium hydroxide hydrate (1.2 equivalents) was dissolved in 1, 4-dioxane: water (4/1: v/v) and stirred at room temperature for 3 hours. The reaction mixture was neutralized with 2N aqueous HCl and extracted with ethyl acetate. The organics were dried and concentrated in vacuo to afford 3- (1- (4-chlorophenyl) -5- (4-fluorophenyl) -1, 2-dihydro-2-thioimidazol-3-yl) propionic acid.
Part 2.preparation of 3- (1- (4-chlorophenyl) -5- (4-fluorophenyl) -1, 2-dihydro-2-thioimidazol-3-yl) -1- (pyrrolidin-1-yl) propan-1-one
To a solution of 3- (1- (4-chlorophenyl) -5- (4-fluorophenyl) -1, 2-dihydro-2-thioimidazol-3-yl) propionic acid (1 eq), 1-3- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.7 eq) and morpholine (1.7 eq) in THF was stirred at room temperature overnight. The reaction was quenched with water and extracted with ethyl acetate. The organics were dried and concentrated in vacuo. The residue was purified by silica column chromatography to give 3- (1- (4-chlorophenyl) -5- (4-fluorophenyl) -1, 2-dihydro-2-thioimidazol-3-yl) -1- (pyrrolidin-1-yl) propan-1-one.
Using the general reaction scheme, the compounds in the tables were prepared in a similar manner as described above.
All references cited herein, whether in printed form, electronic reading form, computer-readable storage medium form, or other form, are expressly incorporated by reference in their entirety, including, but not limited to, abstracts, articles, journals, publications, textbooks, treatises, internet sites, databases, patents, and patent publications.
It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims (19)

1. A compound of general formula (I) or a pharmaceutically acceptable salt thereof:
Figure A2005800073890002C1
wherein,
R3is Ar1Or Ar1-X-Y, wherein
Each Ar1Is cycloalkyl, aryl, heterocyclyl or heteroaryl, each optionally substituted with one or more substituents;
x is NR4，C(R4)2Or O;
y is C ═ O or lower alkyl;
R1is Ar2Or is optionally substituted with Ar2A substituted lower alkyl group,
each Ar2Independently is cycloalkyl, aryl, heterocyclyl or heteroaryl, each optionally substituted with one or more substituents;
each R2Independently selected from (CH)2)mC(O)OR4，(CH2)mC(O)Ar3，(CH2)mC(O)NR4R5，(CH2)nNR4R5，(CH2)3Ar3Or (CH)2)mAr3；
Each R4Independently selected from H or lower alkyl;
each R5Independently selected from H, lower alkyl or (CH)2)pAr3；
m is 1 or 2;
n is 2 or 3;
p is 0 or 1;
each Ar3Is cycloalkyl, aryl, heterocyclyl or heteroaryl, each optionally substituted with one or more substituents;
Ar1、Ar2and Ar3Each substituent of (A) is independently selected from halogen, CN, NO2，OR6，SR6，S(O)2OR6，NR6R7Cycloalkyl radical, C1-C2Perfluoroalkyl radical, C1-C2Perfluoroalkoxy, 1, 2-methylenedioxy, C (O) OR6，C(O)NR6R7，OC(O)NR6R7，NR6C(O)NR6R7，C(NR6)NR6R7，NR6C(NR7)NR6R7，S(O)2NR6R7，R8，C(O)R8，NR6C(O)R8，S(O)R8Or S (O)2R8；
Each R6Independently selected from hydrogen or lower alkyl, said lower alkyl being optionally substituted by one or more groups independently selected from halogen, OH, C1-C4Alkoxy radical, NH2，C1-C4Alkylamino radical, C1-C4Dialkylamino or C3-C6A substituent in a cycloalkyl group;
each R7Independently selected from hydrogen, (CH)2)qAr4Or lower alkyl optionally substituted by one or more substituents independently selected from halogen, OH, C1-C4Alkoxy radical, NH2，C1-C4Alkylamino radical, C1-C4Dialkylamino or C3-C6A substituent in a cycloalkyl group;
each R8Independently selected from (CH)2)qAr4Or lower alkyl optionally substituted by one or more substituents independently selected from halogen, OH, C1-C4Alkoxy radical, NH2，C1-C4Alkylamino radical, C1-C4Dialkylamino or C3-C6A substituent in a cycloalkyl group;
each Ar4Independently selected from C3-C6Cycloalkyl, aryl or heteroaryl, each optionally substituted by one to three substituents independently selected from halogen, OH, C1-C4Alkoxy radical, NH2，C1-C4Alkylamino radical, C1-C4Dialkylamino or C3-C6A substituent in a cycloalkyl group; and
q is 0 or 1.
2. The compound of claim 1, wherein R3Is Ar1And R1Is Ar2。
3. The compound of claim 1 or 2, wherein,
R3independently is aryl or heteroaryl, each optionally substituted by one or moreSubstituent group substitution; and
R1independently aryl or heteroaryl, each optionally substituted with one or more substituents.
4. The compound of any one of claims 1-3, wherein R2Is (CH)2)mC(O)OR4，(CH2)mC(O)Ar3Or (CH)2)mC(O)NR4R5。
5. The compound of any one of claims 1-3, wherein R2Is (CH)2)mAr3，Ar3Is aryl or heteroaryl, each optionally substituted with one or more substituents.
6. The compound of any one of claims 1-3, wherein R2Is (CH)2)mC(O)NR4R5，R5Independently is (CH)2)pAr3Wherein Ar is3Is aryl or heteroaryl, each optionally substituted with one or more substituents.
7. The compound of any one of claims 1-3, wherein R2Is (CH)2)nNR4R5Or (CH)2)mAr3。
8. The compound of claim 1, which is any of the compounds of tables 1-6.
9. A composition comprising a compound of formula I in claim 1 and a pharmaceutically acceptable carrier.
10. The composition of claim 9, further comprising an additional therapeutic agent.
11. A method of treating a disease or disease symptom in a patient in need of such treatment, the method comprising administering to the patient an effective amount of a compound of any one of claims 1-8.
12. The method of claim 11, wherein the disease or disease symptom is modulated by calcium channel Cav2.
13. The method of claim 12, wherein the disease or disease symptom is modulated by calcium channel cav 2.2.
14. The method of claim 11, wherein the disease or disease symptom is angina, hypertension, congestive heart failure, myocardial ischemia, arrhythmia, diabetes, urinary incontinence, stroke, pain, brain trauma, or a neuronal disorder.
15. A method of modulating calcium channel activity, comprising contacting a calcium channel with a compound of formula I according to claim 1.
16. A method of modulating the activity of calcium channel Cav2 in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 8.
17. A method of modulating the activity of the calcium channel Cav2 in a patient, the method comprising administering to the patient a therapeutically effective amount of the composition of claim 9.
18. The compound of claim 5, wherein m is 2 and Ar3Is heteroaryl, comprising a five-membered ring containing carbon atoms and 1, 2 or 3 heteroatoms selected from N, O and S, and optionally substituted with one or more substituents.
19. The compound of claim 18, wherein Ar3Is pyrrolidinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, each optionally substituted with one or more substituents.
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